Amiodarone, a drug that is effective in the treatment of intractable cardiac arrhythmias, can cause potentially life-threatening pulmonary toxicity. Utilizing an animal model that we developed, we found that Fischer rats fed 175 mg/kg of amiodarone for three weeks or longer developed both pulmonary inflammation and phospholipidosis, whereas Wistar rats fed the same drug dose did not. Amiodarone toxicity was dose dependent and correlated with the amount of drug, metabolite, and phospholipid that accumulated in the lungs. In addition, we found that Fischer rat whole lung homogenates and alveolar macrophages took up more amiodarone than Wistar rat lung homogenates and that amiodarone was more cytotoxic to Fischer fibroblasts than Wistar fibroblasts. Therefore, at least part of the pathogenesis of amiodarone pulmonary toxicity is related to direct drug cytotoxicity, and strain differences in susceptibility ar related to the ability to take up drug and metabolite into the lung. Amiodarone also interferes with several different cellular functions, including the development of cell-mediated immunity, phagocytic ability, and alveolar macrophage production superoxide. Our hypothesis is that these and other cellular functions are affected by amiodarone or the major metabolite of amiodarone, N-desethylamiodarone (N-des), because the drug alters both metabolism and calcium homeostasis which interferes with receptor-mediated signal transduction. Supporting evidence for this hypothesis is that amiodarone inhibits phospholipase C in vitro and absent spleen cell mitogen responses in drug-fed rats can be partially restored by activation with a combination of inonomycin and phorbol ester. The present study will investigate the specific mechanisms by which amiodarone affects lipid synthesis, signal transduction, and calcium homeostasis. In addition, we will determine whether alterations in lipid metabolism and increased calcium flux ar related to cytotoxicity by comparing responses in fibroblasts isolated from the two strains. These studies are important because, if amiodarone inhibits cellular functions such as the generation of an immune response, the increased susceptibility to pulmonary infection could exacerbate amiodarone toxicity. Furthermore, increased knowledge of signal transduction, especially in the macrophage, should be gained from these studies.